Hydroxy-amino acid amides

ABSTRACT

Compounds of Formula I ##STR1## are disclosed as inhibitors of plasmepsin and cathepsin D. The compounds are therefore useful to treat diseases such as malaria. In preferred compounds of formula I, Y is the residue of an N-acylated amino acid, a substituted 4-aminoproline or a substituted piperazinealkanoic acid. Intermediates in the solid phase synthesis of compounds of formula I, in which the compounds are attached to a solid support, are also disclosed.

FIELD OF THE INVENTION

The present invention relates to amino acid (statine) analogs thatdisplay selective inhibitory activity against plasmepsin and cathepsinD.

BACKGROUND OF THE INVENTION

Resistance to known antimalarial therapies is becoming an increasingproblem and new therapies are therefore desperately needed. Uponinfecting a host, the malaria parasite avidly consumes the hosthemoglobin as its source of nutrients. Plasmepsin I and II are proteasesfrom Plasmodium falciparum that are necessary during the initial stagesof hemoglobin hydrolysis and digestion, which primarily occurs in theα-chain, between Phe 33 and Leu 34, although other sites may serve assubstrates for hydrolysis as well. It has been shown in culturesinhibition of plasmepsin by a peptidomimetic inhibitor is effective inpreventing malarial hemoglobin degradation and in killing the parasite(Francis, S. E., Gluzman, I. Y. Oksman, A., Knickerbocker, A., Mueller,Bryant, M. L., Sherman, D. R., Russell, D. G., and Goldberg, D. E.(1994) EMBO J, 13, 306-317). Thus, persons of skill in the art expectthat plasmepsin inhibitors will provide effective antimalarial therapy.

Cathepsin D is a human protease in the endosomal-lysosomal pathway,involved in lysosomal biogenesis and protein targeting, and may also beinvolved in antigen processing and presentation of peptide fragments.The protease therefore displays broad substrate specificity but prefershydrophobic residues on either side of the scissile bond.

Cathepsin D has been implicated in a variety of diseases, includingcorrective tissue disease, muscular dystrophy, and breast cancer. Mostrecently, cathepsin D is believed to be γ-secretase, the protease whichprocesses the β-amyloid precursor protein to generate the C-terminus ofβ-amyloid (Dreyer, R. N., Bausch, K. M., Fracasso, P., Hammond, L. J.,Wunderlich, D., Wirak, D. O., Davis, G., Brini, C. M., Bucholz, T. M.,Konig, G., Kamark, M. E., and Tamburini, P. P. (1994) Eur. J. Biochem.,224, 265-271 and Ladror, U. S., Synder, S. W., Wang, G. T., Holzman, andKrafft, G. A. (1994) J. Biol. Chem., 269, 18422-18428), which is themajor component of plaque in the brains of Alzheimer's patients.Consequently, persons of skill in the art expect that inhibitors ofcathepsin D will be useful in treating Alzheimer's disease.

The present invention relates to amino acid (statine) analogs and theirinhibitory action against aspartyl proteases, and more particularly, theinvention relates to the identification of amino acid analogs thatdisplay selective inhibitory activity against plasmepsin and cathepsinD. Although statine-containing peptides are known which inhibit aspartylproteases (Shewale, J. G.; Takahashi, R.; Tang, J., Aspartic Proteinasesand Their Inhibitors, Kostka, V., Ed. Wlater de Gruyter: Berlin (1986)pp 101-116), there are only a few selective inhibitors for cathepsin D(Lin, T. Y.; Williams, H. R., Inhibition of Cathepsin D by SyntheticOligopeptides, J. Biol. Chem. (1979), 254, 11875-11883; Rich, D. H.;Agarwal, N. S., Inhibition of Cathepsin D by Substrate AnaloguesContaining Statine and by Analogues of Pepstatin, J. Med. Chem. (1986)29 (2519-2524), and for plasmepsin (Silva, A. M. et al., Structure andInhibition of Plasmepsin II, A Hemoglobin-Degrading Enzyme FromPlasmodium falciparum, Proceed Natl Acad Sci, 1996, 93, 10034-10039).The present invention also relates to the solid phase synthesis of suchamino acid analogs.

SUMMARY OF THE INVENTION I. Preferred Embodiments

The compounds of the present invention are represented by Formula I:##STR2## wherein: R¹ and R³ are independently chosen from the groupconsisting of alky, alkoxyalkyl and arylalkyl;

R² is H or S--C(O)--L--

wherein:

s is a solid support; and

--L-- is a linker; and

Y is --Aa--C(O)R⁴ or --C(O)R⁵ ;

wherein

Aa is an amino acid attached via its carboxyl to the amine nitrogen ofstructure I;

R⁴ is chosen from the group consisting of alkyl, aryl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl orsubstituted heterocycloalkyl; and

R⁵ is ##STR3## wherein x is 0 or 1;

R⁶ and R⁷ are independently chosen from the group consisting ofsubstituted alkyl, alkylcarbonyl and substituted alkylcarbonyl; and

R⁸ is alkyl.

Preferred compounds of Formula I are those wherein --L-- is of Formula(a) ##STR4## wherein the left-hand bond is the point of attachment to--C(O)-- and the right hand bond is the point of attachment to the amidenitrogen of structure I.

A preferred embodiment of the invention are compounds of Formula I

wherein:

R¹ is chosen from the group consisting of butyl, 3-phenylpropyl and3-methoxypropyl;

Y is --Aa--C(O)R⁴ ;

Aa is chosen from the group consisting of valine, leucine,phenylalanine, isoleucine β-2-thienylalanine, t-butylglycine, cysteineand phenylglycine; and

R⁴ is chosen from the group consisting of ##STR5## Another preferredembodiment of the invention are compounds of Formula I wherein:

R¹ is chosen from the group consisting of methyl, benzyl, butyl,3-phenylpropyl, 3-methoxypropyl, 2-pyridinylmethyl and3-pyridinylmethyl;

Y is --C(O)R⁵ ;

R⁶ is chosen from the group consisting of 3-pyridinylmethyl,phenylethoxyethyl, 3,4,5-trimethoxybenzyl, 4-acetamidobenzyl,4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl, 3-phenylpropyl,3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl, isobutyl, propionyland 3,5-di (trifluoromethyl)phenylacetyl; and

R⁷ is chosen from the group consisting of 4-isopropoxybenzoyl,nicotinoyl, 3,4,5-trimethoxybenzoyl, 3-phenoxybenzoyl,3-(2-methoxyphenyl)propyl, 3,4,5-trimethoxyphenylpropionyl,3,3-diphenylpropionyl, phenylacetyl, 3,4-dichlorophenylacetyl and ethyladipoyl.

A preferred subset of the foregoing embodiment of the invention arecompounds of the Formula I wherein:

R¹ is chosen from the group consisting of methyl, benzyl, butyl,3-phenylpropyl and 3-methoxypropyl;

Y is --C(O)R⁵ ;

R⁵ is ##STR6## R⁶ is chosen from the group consisting of3-pyridinylmethyl, phenylethoxyethyl, 3,4,5-trimethoxybenzyl,4-acetamidobenzyl, 4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl,3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl and 3-phenylpropyl;and

R⁷ is chosen from the group consisting of 4-isopropoxybenzoyl,nicotinoyl, 3,4,5-trimethoxybenzoyl, 3-phenoxybenzoyl,3-(2-methoxyphenyl)propyl, 3,4,5-trimethoxyphenylpropionyl,3,3-diphenylpropionyl, 3,4-dichlorophenylacetyl and ethyl adipoyl.

A second subset of the second preferred embodiment of the invention arecompounds of Formula I wherein

R¹ is chosen from the group consisting of butyl, 2-pyridinylmethyl and3-pyridinylmethyl;

R⁵ is ##STR7## R⁶ is chosen from the group consisting of 4-phenylbenzyl,isobutyl, propionyl and 3,5-di(trifluoromethyl)phenylacetyl;

R⁷ is chosen from the group consisting of phenylacetyl, 3-phenoxybenzoyland 3,3-diphenylpropionyl; and

R⁸ is ethyl.

Another aspect of the invention is the use ofdivinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrenebeads optionally functionalized with amino groups (e.g., TentaGel™ SNH₂, Rapp Polymere) as the solid supports for constructing compounds ofFormula I.

DETAILED DESCRIPTION OF THE INVENTION II. Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningthroughout:

Alloc=allyloxy carbonyl

Bn=benzyl

BNB=4-bromomethyl-3-nitrobenzoic acid

BOC=t-butyloxy carbonyl

Bu=butyl

c-=cyclo

DCM=Dichloromethane=methylene chloride=CH₂ Cl₂

DIC=diisopropylcarbodiimide

DIEA=diisopropylethyl amine

DMAP=4-N,N-dimethylaminopyridine

DMF=N,N-dimethylformamide

DVB=1,4-divinylbenzene

Et=ethyl

Fmoc=9-fluorenylmethoxycarbonyl

HATU=O-(7-Azabenzotriazol-1-yl)1,1,3,3-tetramethyluroniumhexafluorophosphate

HOAc=acetic acid

HOBt=hydroxybenzotriazole

m-=meta

Me=methyl

N₃ =azido

NaBH₃ CN=sodium cyanoborohydride=SCB

PEG=polyethylene glycol

Ph=phenyl

s-=secondary

t-=tertiary

TFA=trifluoroacetic acid

THF=tetrahydrofuran

"Alkyl" is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. "Lower alkyl" means alkyl groups offrom 1 to 8 carbon atoms. Examples of lower alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, s-and t-butyl, pentyl hexyl, octyl,cyclopropylenthyl, bornyl and the like. Preferred alkyl groups are thoseof C₂₀ or below. "Cycloalkyl" is a subset of alkyl and includes cyclichydrocarbon groups of from 3 to 8 carbon atoms. Examples of lowercycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and thelike.

"Alkenyl" includes C₂ -C₈ unsaturated hydrocarbons of a linear,branched, or cyclic (C₅ -C₆) configuration and combinations thereof.Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl,hexenyl, c-hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and thelike.

"Alkynyl" includes C₂ -C₈ hydrocarbons of a linear or branchedconfiguration and combinations thereof containing at least onecarbon-carbon triple bond. Examples of alkynyl groups include ethane,propyne, butyne, pentyne, 3-methyl-1-butyne, 3,3-dimethyl-1-butyne andthe like.

"Alkoxy" refers to groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration and combinations thereof. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like.

"Acylamino" refers to acylamino groups of from 1 to 8 carbon atoms of astraight, branched or cyclic configuration and combinations thereof.Examples include acetylamino, butylamino, cyclohexylamino and the like.

"Halogen" includes F, Cl, Br, and I.

"Aryl" and "heteroaryl" mean a 5- or 6-membered aromatic orheteroaromatic ring containing 0-3 heteroatoms selected form O, N, andS; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring systemcontaining 0-3 heteroatoms selected from O, N, and S; or a tricyclic 13-or 14-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, and S; each of which rings is optionallysubstituted with 1-3 lower alkyl, substituted alkyl, substitutedalkynyl, ═O, --NO₂, halogen, hydroxy, alkoxy, OCH(COOH)₂, cyano, NR¹⁰R¹⁰, acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, andheteroaryl or heteroaryloxy; each of said phenyl, benzyl, phenoxy,benzyloxy, heteroaryl, and heteroaryloxy is optionally substituted with1-3 substituents selected from lower alkyl, alkenyl, alkynyl, halogen,hydroxy, alkoxy, cyano, phenyl, benzyl, benzyloxy, carboxamido,heteroaryl, heteroaryloxy, NO₂, and NR¹⁰ R¹⁰ ;

R¹⁰ is independently let, lower alkyl or cycloalkyl, and --R¹⁰ R¹⁰ maybe fused to form a cyclic ring with nitrogen.

The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene,naphthalene, indane, tetralin, and fluorene and the 5- to 10-memberedaromatic heterocyclic rings include, e.g., imidazole, pyridine, indole,thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline,isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, andpyrazole.

"Arylalkyl" means an alkyl residue attached to an aryl ring. Examplesinclude, e.g., benzyl, phenethyl and the like.

"Heteroarylalkyl" means an alkyl residue attached to a heteroaryl ring.Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.

"teterocycloalkyl" means a cycloalkyl where one to two of the methylene(CH₂) groups is replaced by a heteroatom such as O, NR' (wherein R' is Hor alkyl), S or the like; with the proviso that when two heteroatoms arepresent, they must be separated by at least two carbon atoms. Examplesof heterocycloalkyls include tetrahydrofuranyl, piperidine, dioxanyl andthe like.

"Carboxyalkyl" means --C(O)R", wherein R" is alkyl.

"Substituted" alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkylmeans alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl wherein upto three H atoms on each C atom therein are replaced with halogen,hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano,carbonyl, NO₂, NR⁹ R⁹ (wherein R⁹ is H, alkyl or arylalkyl), alkylthio,sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl,phenoxy, benzyloxy, heteroaryloxy, and substituted phenyl, benzyl,heteroaryl, phenoxy, benzyloxy or heteroaryloxy.

Aa represents an amino acid and is intended to include the racemates andall optical isomers thereof. The amino acid side chains of Aa include,e.g., methyl (alanine), hydroxymethyl (serine), phenylmethyl(phenylalanine), thiomethyl (cysteine), carboxyethyl (glutamic acid),etc. Primary and secondary amino acids are intended to include alanine,asparagine, N-β-trityl-asparagine, aspartic acid, asparticacid-β-t-butyl ester, arginine, N^(g) -Mtr-arginine, cysteine,S-trityl-cysteine, glutamic acid, glutamic acid-γ-t-butyl ester,glutamine, N-γ-trityl-glutamine, glycine, histidine, N^(im)-trityl-histidine, isoleucine, leucine, lysine, N.sup.ε -Boc-lysine,methionine, phenylalanine, proline, serine, O-t-butyl-serine, threonine,tryptophan, N^(in) -Boc-tryptophan, tyrosine, valine, sarcosine,L-alanine, chloro-L-alanine, 2-aminoisobutyric acid,2-(methylamino)isobutyric acid, D, L-3-aminoisobutyric acid, (R)-(-)-2aminoisobutyric acid, (S)-(+)-2-aminoisobutyric acid, 2-thienyalanine,D-norvaline, L-norvaline, L-2-amino-4-pentenoic acid, D-isoleucine,L-isoleucine, D-norleucine, 2,3-diaminopropionic acid, L-norleucine,D,L-2-aminocaprylic acid β-alanine, D,L-3-aminobutyric acid,4-aminobutyric acid, 4-(methylamino)butyric acid, 5-aminovaleric acid,5-aminocaproic acid, 7-aminoheptanoic acid, 8-aminocaprylic acid,11-aminodecanoic acid, 12-aminododecanoic acid, carboxymethoxylamine,D-serine, D-homoserine, L-homoserine, D-allothreonine, L-allothreonine,D-threonine, L-threonine, D,L-4-amino-3-hydroxybutyric acid,D,L-3-hyroxynorvaline, (3S,4S)-(-)-statine, 5-hydroxy-D,L-lysine,1-amino-1-cyclopropanecarboxylic acid, 1-amino-1-cyclopentanecarboxylicacid, 1-amino-1-cyclohexanecarboxylic acid,5-amino-1,3-cyclohexadiene-1-carboxylic acid,2-amino-2-norbornanecarboxylic acid, (S)-(-)-2-azetidinecarboxylic acid,cis-4-hydroxy-D-proline, cis-4-hydroxy-L-proline,trans-4-hydroxy-L-proline, 3-4-dehydro-D,L-proline,3,4-dehydro-L-proline, pipecolic acid, pipecolinic acid, nipecotic acid,isonipecotic acid, mimosine, citrulline, 2,3-diaminopropionic acid,D,L-2,4-diaminobutyric acid, (S)-(+)-diaminobutyric acid, ornithine,2-methylornithine, N-ε-methyl-L-lysine, N-methyl-D-aspartic acid,D,L-2-methylglutamic, D,L-2-aminoadipic acid, D-2-aminoadipic acid,naphthylalanine, L-2-aminoadipic acid, (+/-)-3-aminoadipic acid,D-cysteine, D-penicillamine, L -penicillamine, D,L-homocysteine,S-methyl-L-cysteine, L-methionine, D-ethionine, L-ethionine,S-carboxymethyl-L-cysteine, (S)-(+)-2-phenylglycine,(R)-(-)-2-phenylglycine, N-phenylglycine, N-(4-hydroxyphenyl)glycine,D-phenylalanine, (S)-(-)indoline-2-carboxylic acid,α-methyl,D,L-phenylalanine, β-methyl-D,L-phenylalanine,D-homophenylalanine, L-homophenylalanine, D,L-2-fluorophenylglycine,D,L-2-fluorophenylalanine, D,L-3-fluorophenylalanine,D,L-4-fluorophenylalanine, D,L-4-chlorophenylalanine,L-4-chlorophenylalanine, 4-bromo-D,L-phenylalanine,4-iodo-D-phenylalanine, 3,3', 5-triiodo-L-thyronine, (+)-3,3',5-triiodo-L-thyronine sodium salt, D-thyronine, L-thyronine,D,L-m-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-tyrosine,o-methyl-L-tyrosine, 3-fluoro-D,L-tyrosine, 3-iodo-L-tyrosine,3-nitro-L-tyrosine, 3,5-diiodo-L-tyrosine, D,L-dopa, L-dopa,2,4,5-trihydroxyphenyl-D,L-alanine, 3-amino-L-tyrosine,4-amino-D-phenylalanine, 4-amino-L-phenylalanine,4-amino-D,L-phenylalanine, 4-nitro-L-phenylalanine,4-nitro-D,L-phenylalanine, 3,5-dinitro-L-tyrosine, D,L-α-methyltyrosine,L-α-methyltyrosine, (-)-3-(3,4-dihydroxyphenyl)-2-methyl-L-alanine,D,L-threo-3-phenylserine, trans-4-(aminomethyl)cyclohexane carboxylicacid, 4-(aminomethyl) benzoic acid, D,L-3-aminobutyric acid, 3-aminocyclohexane carboxylic acid, cis-2-amino-1-cyclohexane carboxylicacid, γ-amino-β-(p-chlorophenyl) butyric acid (Baclofen),D,L-3-aminophenylpropionic acid, 3-amino-3-(4-chlorophenyl) propionicacid, 3-amino-3-(2-nitrophenyl)propionic acid, cyclohexylalanine,t-butylglycine, pyridylalanine and 3-amino-4,4,4-trifluorobutyric acid.

The statine residues used in this invention were prepared by the methodof Rich (Rich et al., J. Org. Chem., 43, 3624 (1978)).

The material upon which the combinatorial syntheses of the invention areperformed are referred to as solid supports, beads or resins. Theseterms are intended to include beads, pellets, disks, fibers, gels, orparticles such as cellulose beads, poreglass beads, silica gels,polystyrene beads optionally cross-linked with divinylbenzene andoptionally grafted with polyethylene glycol and optionallyfunctionalized with amino, hydroxy, carboxy, or halo groups, graftedco-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamidebeads optionally cross-linked with N,N'-bis-acryloyl ethylene diamine,glass particles coated with hydrophobic polymer, etc., i.e., materialhaving a rigid or semi-rigid surface; and soluble supports such as lowmolecular weight non-cross-linked polystyrene.

III. Optical Isomers-Diastereomers-Geometric Isomers

Some of the compounds described herein contain one of more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisometric forms which may be defined in terms of absolutestereochemistry as (R)- or (S)- , or as (D)- or (L)- for amino acids.The present invention is meant to include all such possiblediastereomers, as well as their racemic and optically pure forms.Optically active (R)- and (S), or (D)- and (L)- isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are intended to beincluded.

IV. Assays for Determining Biological Activity

1. Method for Plasmepsin II

The assay mix contained 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA,0.01% Tween 20, 12.5% glycerol, 18 % DMSO and 12 μM plasmepsinsubstrate. Twenty five μL of the assay mix was added to each well of a96-well microtiter plate containing dried down bead eluate or emptycontrol wells. The plates were then sonicated and mixed. 25 μL of 8 nMplasmepsin II, in 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA, 0.01%Tween 20, and 12.5% glycerol, was added to the assay mix. The finalconcentrations were 4 nM plasmepsin II, 6 μM plasmepsin substrate, 9%DMSO, 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA, 0.01% Tween 20, and12.5% glycerol. The reaction was incubated for 10 minutes at 25° C. andthen quenched by the addition of 25 μL of 1M Tris (pH 8.5) and 50 % DMSOto achieve a final concentration of 0.33M Tris and 23% DMSO. The EDANSfluorescence was measured using a Tecan, SLT FluoStar fluorescence platereader with an excitation filter of 350 nm and an emission filter 510nm. The background was determined by 25 μL of 50 mM sodium acetate (pH5.0), 1 mg/ml BSA, 0.01% Tween 20, and 12.5% glycerol without enzyme.

2. Method for Cathepsin D

The assay mix contained 25 mM sodium formate (pH 3.5), 1 mg/ml BSA, 12%DMSO and 12 μM cathepsin D substrate. Twenty five μL of the assay mixwere added to each well of a 96-well microliter plate containing drieddown bead eluate or empty control wells. The plates were then sonicatedand mixed. 25 μL of 1.6 nM cathepsin D, in 25 mM sodium formate (pH3.5), and 1 mg/ml BSA, was added to the assay mix. The finalconcentrations were 0.8 nM cathepsin D, 6 μM cathepsin D substrate, 6%DMSO, 25 mM sodium formate (pH 3.5), and 1 mg/ml BSA. The reaction wasincubated for 10 minutes at 25° C. and then quenched by the addition of25 μL of 1M Tris (pH 8.5) and 50% DMSO to achieve a final concentrationof 0.33 M Tris and 21% DMSO. The EDANS fluorescence was measured asstated herein above. The background was determined by 25 μL of 50 mMsodium formate (pH 3.5), and 1 mg/ml BSA without enzyme.

V. Methods of Synthesis

The compounds of the present invention may be prepared according to thefollowing methods. In carrying out the syntheses, one typically beginswith a quantity of solid support that will provide enough compound aftercleavage from the solid support for biological testing in the hereindescribed assays. In the case where the solid support is TentaGel™, itis recommended that approximately 0.5 g of beads of about 180 microns indiameter, with a loading capacity of about 300 picoM per bead, be used.As the chemical yield of compounds after photolysis typically rangesfrom approximately 20% up to 60%, this quantity will provide a yield(approximately>10 mg) sufficient for biological testing in the givenprotease assays. For actual synthesis, the appropriate reagents andreaction conditions are applied to a reaction vessel containing thespecified quantity of beads. During the syntheses, the beads may bewashed free of any excess reagents or by-products before proceeding tothe next reaction. At the end of a given reaction sequence, the beadsare suspended in a suitable solvent such as methanol and exposed to UVlight (365 nm) for 3 hours at room temperature. This protocol releasesthe compounds of Formula I (wherein R² is H) for purification andbiological testing.

A. Scheme 1: Derivatizing resin with bis-Boc lysine

A batch of amino-functionalized PEG-grafted polystyrene beads 3, e.g.,TentaGel™ 3 amine may be modified with bis-Boc lysine 2 to increase theavailable reaction sites for ligand attachment. Bis-Boc lysine 2 iscoupled to the amino-functionalized beads 3 by amide bond formation.Coupling is achieved by reacting a suspension of beads in DCM and adding2, HOBt and DIC. The suspension is shaken overnight, drained orfiltered, and then washed in succession with DMF, MeOH and DCM, yieldingderivatized resin 1 which is then dried overnight under vacuum.

B. Scheme 2

The various amine choices (see Tables 1 and 2) are added to the reactionvessel containing resin 1. The amines are attached to resin 1 throughthe photo-labile linker, 4-bromomethyl-3-nitrobenzoic acid. Thisattachment is accomplished in two steps.

Step 1. The Boc protecting group on resin 1 is removed and the BNB isattached by the following method. A suspension of resin 1 in 1:1 TFA/DCMis shaken for about 1 hour, then washed with DCM, MeOH, 4:1 MeOH/Et₃ N,MeOH, DMF and then DCM. The resultant bis-amine resin 4 is suspended inDCM, and treated with a solution of BNB, HOBt and DIC in DCM. Thesuspension is shaken for about 3 hours, then drained and washed withDCM. The BNB resin 6 is dried overnight under vacuum.

Step 2. The BNB resin 6 from step 1 are reacted with a unique primaryamine (see Tables 1 and 2) to generate compound 7. The coupling of theamine to resin 6 occurs through displacement of the linker bromide andformation of a new carbon-nitrogen bond. As a quality control for thereaction in this step, a small portion of each batch of resin may beremoved and titrated with picric acid to determine the extent of amineloading.

C. Scheme 3

Amine 7 is then treated with one of the hydroxy-amino acid reagents(statines) 8 (see Tables 1 and 2). Each hydroxy-amino acid 8 is coupledto amine resin 7 by amide bond formation to produce compound 9.

Compounds 9 may be directed through either the chemistry of Schemes 4and 5, yielding compounds as in Example 1 and found in Table 1, or inthe alternative, through the chemistry of Schemes 6, 7 and 8, yieldingcompounds as in Example 2 and Table 2.

D. Scheme 4 (With Scheme 5, yields compounds as in Example 1)

Resin 9 is treated with TFA/DCM to remove the Boc protecting group, thusexposing the terminal amino group and forming compounds 10. Eachreaction vessel is then treated with one amino acid 11 (see Table 1),for separate coupling of each amino acid to compound 10 by amide bondformation to produce compounds 12. The amino acids are introduced withthe base-labile Fmoc on the alpha-nitrogen atom.

E. Scheme 5

Compounds 12 are treated with piperidine/DMF to deprotect the aminogroup by removing the Fmoc protecting group, thus giving rise tocompounds 13, which in turn are treated with one carboxylic acid (seeTable 1), which couples with compound 13 to generate compounds 14. Resin14 may be cleaved by exposing it to UV light (ca. 360 nm) for 15-180minutes at 25°-50° C. in a suitable solvent such as methanol to produceamides of Formula I (wherein R² is H), as in Example 1 and Table 1.

Scheme 6 (With Schemes 7 and 8, yields compounds as in Example 2)

Resin 9 (from Scheme 3) is treated with TFA/DCM to remove the Bocprotecting group, thus exposing the terminal amino group and formingcompounds 10. The compound is then treated with one diamino acid 17(Table 2), for separate coupling of each diamino acid 17 to compounds 10by amide bond formation, using HATU and DIEA, to produce compounds 18.

G. Scheme 7

Resin 18 is treated with TFA/DCM to selectively remove the Bocprotecting group on the diamino acid ligand to produce amines 19. Theresin is then treated with one carboxylic acid reagent or onecarboxyaldehyde (see Table 2) for either separate coupling of eachcarboxylic acid to compound 19 by amide bond formation or separatereductive amination of each carboxyaldehyde to compound 19 with sodiumcyanoborohydride in methanol to produce resin 20.

H. Scheme 8

Compounds 20 are then treated with palladium tetrakistriphenylphosphine,tributyltin hydride in acetic acid and DCM to selectively remove theAlloc protecting group on the diamino acid ligand to produce amines 21.Each vessel is then treated with one carboxylic acid reagent (see Table2) for separate coupling of the carboxylic acid to compounds 21 by amidebond formation to produce resin 22. Resin 22 may be cleaved by exposingthe resin to UV light (ca. 360 nm) for 15-180 minutes at 25°-50° C. in asuitable solvent such as methanol to produce amides Formula I (whereinR² is H), as in Example 2 and Table 2.

I. Scheme 9

Diamino acid intermediate 23, one of the diamine ligands (Table 2), isprepared from hydroxy proline 24 by first treating it withalloxychloroformate, in a solvent such as water, in the presence of abase, e.g., potassium carbonate to yield Alloc protected compound 25.Compound 25 is esterified with either acid in methanol or diazomethanein diethyl ether, producing ester 26, which is then converted to bromidecompound 27 using a brominating reagent such as triphenylphosphine andcarbon tetrabromide. The bromide substituent is in turn displaced withazide using either sodium or potassium azide in DMF. Resultant azidecompound 28 is then reductively alkylated with acetaldehyde, by firsttreating it with triphenylphosphine to generate an imine which is inturn reduced to an N-ethyl amino group in compound 29. Amine 29 istreated with Boc anhydride in acetonitrile to produce compound 30 whichin turn is hydrolyzed to carboxylic acid compound 23 by the action oflithium hydroxide in water.

EXAMPLE 1 Entry 11, Table 1 ##STR8## Step 1--Sequential Attachment ofbis-Boc Lysine, Photo-labile Linker and an Amine

1a. Attachment of bis-Boc Lysine to TentaGel™

TentaGel™ resin (S-NH₂, 1.0 g, 0.029 mmol/g, 0.29 mmol, 180-220 um) wassuspended in a solution of bis-Boc lysine (0.87 mmol, 0.5 g), and HOBt(0.87 mmol, 0.12 g), then treated with DIC (01.7 mmol, 0.27 mL). Thesuspension was shaken overnight, then drained and washed with 15 mL eachDMF (3×), MeOH (3×) and DCM (3×).

1b. Removal of Boc Protecting Group and Attachment of Photo-labileLinker

A suspension of resin 1 (1.0 g) in 1:1 TFA/DCM was shaken for 1 hour,then washed with 50 mL each DCM (3×), MeOH (3×), 4:1 MeOH/Et₃ N (1×),MeOH (3×), DMF (3×), then DCM (3×). This resin was then suspended in 25mL DCM, then treated with a pre-incubated (45 min) solution of4-bromomethyl-3-nitro benzoic acid (1.5 mmol, 0.40 g), HOBt (1.5 mmol,0.23 g), DIC (3.2 mmol, 0.5 mL) in DCM (25 mL). The suspension wasshaken for 3 hours, then drained and washed with three 50 mL portions ofDCM.

1c. Addition of Amine

One gram of the step 1b resin was suspended in THF (50 mL) and thentreated with butylamine (5.4 mmol) and shaken overnight. The resin wasthen drained and washed with 50 mL each DMF (3×), MeOH (3×), 10:1MeOH/TFA (1×), MeOH (3×), DMF (3×), then DCM (3×).

Step 2--Addition of Phenylalanine-Derived Statine.

A suspension of the step 1c resin (1.0 g) in DMF (15 mL) was treatedwith the phenylalanine-derived Boc-protected statine (1.3 mmol), DIEA(2.6 mmol, 0.44 mL), then HATU (1.3 mmol, 0.5 g). This suspension wasshaken for 6 hours, drained and washed with 15 mL portions of DMF (3×),MeOH (3×), DMF (3×), and DCM (3×). The dried resin 9 was divided intotwo portions.

Step 3--Deprotection and Attachment of Fmoc Valine

A suspension of resin 9 (0.5 g) in 40% TFA/DCM was shaken for 1 hour,then drained and washed with 50 mL each DCM (3×), MeHt (3×), 10% Et₃N/MeOH (1×), MeOH (3×), and DMF (3×). The product (0.5 g; 0.33 mmol) wassuspended in 10 mL of DMF, containing Fmoc-valine (0.48 mmol) and HATU(0.48 mmol). The suspension was shaken at room temperature for 10minutes and then DIEA (0.99 mmol) was added. The resulting mixture wasshaken for 2 hours, continuously monitoring the resin from the vesselwith the Kaiser test to determine the absence of amine functionality.Once the coupling was complete (Kaiser test negative), the resin wasfiltered and washed with 10 mL portions of DMF (3×), MeOH (3×) and DCM(3×).

Step 4--Fmoc-Deprotection.

The resin (0.5 g) was suspended in 30% piperidine in DMF (15 mL) andshaken for 1 hour at room temperature. The resin was filtered, washedwith 15 mL portions of DMF (2×), DCM (3×), MeOH (3×) and DCM (5×), thendried under vacuum.

Step 5--Attachment of 2,4-dimethoxybenzoic acid

The resin in a reaction vessel was combined with 2,4-dimethoxybenzoicacid (0.6 mmol), HATU (0.72 mmol) and DIEA (1.8 mmol) in DMF (15 mL).The resulting suspension of resin was shaken for approximately one hourat room temperature, at which time the Kaiser test was negative. Theresin was filtered and washed with 10 mL each DMF (2×), MeOH (3×) andDCM (5×). The resin was filtered and subjected to a wash cycleconsisting of 10 mL portions each TFA/water (1:1) (2×), DMF (2×), MeOH(4×), DMF (2×) and DCM (5×), then dried in vacuum.

Step 6--Cleavage by light

The resin was suspended in MeOH (20 mL) and the compound cleaved fromthe resin at 50° C., then light (365 nm) was shone on them for 3 to 4hours. The suspension was filtered, the MeOH removed to give the titlecompound as confirmed by mass spectroscopy (mass spectrum (fab): m/z=528(MH⁺)).

EXAMPLE 2 Entry 16, Table 2 ##STR9## Step 1--Deprotection and Attachmentof Diamino Acid

A suspension of resin 9 (0.5 g) in 40% TFA/DCM, prepared as in Example1, with the exception that 3-methoxypropylamine was used in place ofbutylamine, was shaken for 1 hour, then drained and washed with 50 mLportions of DCM (3×), MeOH (3×), 10% Et₃ N/MeOH (1×), MeOH (3×) and DMF(3×). A suspension of this resin in DMF (50 mL) was treated with thecorresponding diamino carboxylic acid (entry 16, Table 2; 1.6 mmol),DIEA (3.3 mmol), then HATU (1.7 mmol). The suspension was shaken for 6hours, then drained and washed with 50 mL portions of DMF (3×), MeOH(3×), DMF (3×), then DCM (3×) and filtered. The resin was dried invacuo.

Step 2--Deprotection and Attachment of a Carboxyaldehyde

A suspension of resin batch one (0.5 g) in 40% TFA/DCM (10 mL) wasshaken for 1 hour, then drained and washed with 10 mL portions of DCM(3×), MeOH (3×), 10% Et₃ N/MeOH (1×), MeOH (3×), and DMF (3×). Thisresin, suspended in 2% HOAc/DMF (10 mL), was treated with3-phenylpropionyl (8.8 mmol), followed by the addition of NaBH₃ CN (4.4mmol, 0.28 g). The resin was shaken overnight, then drained and washedwith 10 mL portions of DMF (3×), MeOH (3×), then DMF (3×), DCM (3×). Theresin was dried in vacuo.

Step 3--Deprotection and Attachment of3-(2,3,4-Trimethoxyphenyl)Propionoic Acid

A suspension of resin (0.5 g) in DCM (10 mL) was treated with HOAc (4.8mmol, 0.27 mL), Pd(PPh₃)₄ (0.072 mmol, 83 mg), then Bu₃ SnH (2.4 mmol,0.64 mL). This suspension was shaken for 1 hour, then drained and washedwith 10 mL portions of DCM (3×), pyridine (3×), DCM (3×), then DMF (3×).The resin in DMF (10 mL) was then treated with3-(2,3,4-trimethoxyphenyl)propionoic acid (0.36 mmol), followed by DIEA(0.72 mmol, 0.13 mL), and HATU (0.36 mmol, 0.14 g). This suspension wasshaken for 6 hours, then drained and washed with 10 mL portions of DMF(3×), MeOH (3×), then DMF (3×) and DCM (3×).

Step 4--Cleavage by Light

The resin was suspended in MeOH (20 mL) and the compound cleaved fromthe resin at 50° C., then light (365 nm) was shone on them for 3 to 4hours. The suspension was filtered, the MeOH removed to give the titlecompound as confirmed by mass spectroscopy (mass spectrum (fab): m/z=719(MH⁺)).

Using these methods, compounds in Tables 1 and 2 were prepared. Thecompounds in Tables 1 and 2 typically show greater than 2-foldselectivity for either plasmepsin or cathepsin D at an inhibitoryactivity (IC50) less than 10 micromolar.

                                      TABLE 1                                     __________________________________________________________________________    R Groups for Compounds of Formula I where Y is an amino acid                   ##STR10##                                                                    Entry                                                                            R.sup.1 R.sup.3                                                                              R.sup.9 R.sup.4                                             __________________________________________________________________________     1 butyl   CH.sub.2 Ph                                                                          CH(Me)CH.sub.2 Me                                                                      ##STR11##                                           2 butyl   CH.sub.2 Ph                                                                          CH(Me)CH.sub.2 Me                                                                      ##STR12##                                           3 3-phenylpropyl                                                                        CH.sub.2 Ph                                                                          CH(Me)CH.sub.2 Me                                                                      ##STR13##                                           4 butyl   CH.sub.2 CH(Me).sub.2                                                                CH(Me).sub.2                                                                          octyl                                                5 3-phenylpropyl                                                                        CH.sub.2 CH(Me).sub.2                                                                CH(Me)CH.sub.2 Me                                                                      ##STR14##                                           6 3-phenylpropyl                                                                        CH.sub.2 CH(Me).sub.2                                                                CH(Me)CH.sub.2 Me                                                                      ##STR15##                                           7 butyl   CH.sub.2 Ph                                                                          CH(Me).sub.2                                                                           ##STR16##                                           8 3-phenylpropyl                                                                        CH.sub.2 Ph                                                                          CH(Me).sub.2                                                                           ##STR17##                                           9 3-phenylpropyl                                                                        CH.sub.2 Ph                                                                          CH(Me)CH.sub.2 Me                                                                      ##STR18##                                          10 3-phenylpropyl                                                                        CH.sub.2 Ph                                                                          CH(Me)CH.sub.2 Me                                                                      ##STR19##                                          11 butyl   CH.sub.2 Ph                                                                          CH(Me).sub.2                                                                           ##STR20##                                          12 butyl   CH.sub.2 CH(Me).sub.2                                                                Ph                                                                                     ##STR21##                                          13 3-methoxypropyl                                                                       CH.sub.2 CH(Me).sub.2                                                                CH.sub.2 SH                                                                            ##STR22##                                          14 butyl   CH.sub.2 CH(Me).sub.2                                                                CH.sub.2 CH(Me).sub.2                                                                  ##STR23##                                          15 butyl   CH.sub.2 CH(Me).sub.2                                                                CH.sub.2 Ph                                                                            ##STR24##                                          16 butyl   CH.sub.2 CH(Me).sub.2                                                                CH.sub.2 (2-thienyl)                                                                   ##STR25##                                          17 butyl   CH.sub.2 Ph                                                                          Ph                                                                                     ##STR26##                                          18 butyl   CH.sub.2 CH(Me).sub.2                                                                C(Me).sub.3                                                                           (CH.sub.2).sub.3O(2,4-di-Cl)Ph                      19 3-methoxypropyl                                                                       CH.sub.2 Ph                                                                          Ph      (CH.sub.2).sub.3O(2,4-di-Cl)Ph                      20 butyl   CH.sub.2 Ph                                                                          Ph                                                                                     ##STR27##                                          21 butyl   CH.sub.2 Ph                                                                          Ph      (2,4-di-OMe)phenyl                                  __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    R Groups for Compounds of Formula I where Y is the diamino acid                ##STR28##                                                                    Entry                                                                            R.sup.1 R.sup.3                                                                              n R.sup.6      R.sup.7                                      __________________________________________________________________________     1 benzyl  Me     0 3-pyridinylmethyl                                                                          4-isopropoxybenzoyl                           2 butyl   CH.sub.2 Ph                                                                          0 Ph(CH.sub.2).sub.2 O(CH.sub.2).sub.2-                                                      (3,4,5-tri-OMe)benzoyl                        3 butyl   CH.sub.2 Ph                                                                          0 4-phenylbenzyl                                                                             (3,4,5-tri-OMe)benzoyl                        4 butyl   CH.sub.2 Ph                                                                          1 (3,4,5-tri-OMe)benzyl                                                                      4-isopropoxybenzoyl                           5 butyl   CH.sub.2 Ph                                                                          1 (4-MeC(O)NH)PhCH.sub.2                                                                     3-phenoxybenzoyl                              6 3-phenylpropyl                                                                        CH.sub.2 Ph                                                                          0 4-phenylbutyl                                                                              (3,4,5-tri-OMe)benzoyl                        7 butyl   CH.sub.2 Ph                                                                          0 (4-MeC(O)NH)PhCH.sub.2                                                                     (3,4,5-tri-OMe)benzoyl                        8 butyl   CH.sub.2 Ph                                                                          0 3,4-di-Cl-benzyl                                                                           (3,4,5-tri-OMe)benzoyl                        9 butyl   CH.sub.2 Ph                                                                          0 4-phenylbenzyl                                                                             (3,4,5-tri-OMe)benzoyl                       10 butyl   CH.sub.2 Ph                                                                          1 (3,4,5-tri-OMe)benzyl                                                                      3-phenoxybenzoyl                             11 methyl  CH.sub.2 Ph                                                                          0 4-phenylbenzyl                                                                             3-phenoxybenzoyl                             12 3-methoxypropyl                                                                       CH.sub.2 Ph                                                                          1 3,5-bis-trifluoromethylbenzyl                                                              4-isopropoxybenzoyl                          13 butyl   CH.sub.2 Ph                                                                          0 3-phenylpropyl                                                                             (3,4,5-tri-OMe)benzoyl                       14 methyl  CH.sub.2 Ph                                                                          0 4-phenylbenzyl                                                                             3-(2-OMe-phenyl)propyl                       15 methyl  CH.sub.2 Ph                                                                          0 3,4-di-Cl-benzyl                                                                           nicotinoyl                                   16 3-phenylpropyl                                                                        CH.sub.2 Ph                                                                          0 3-phenylpropyl                                                                             (3,4,5-tri-OMe-phenyl)propionyl              17 butyl   CH.sub.2 CH(Me).sub.2                                                                0 3-phenylpropionyl                                                                          3,3-diphenylpropionyl                        18 3-methoxypropyl                                                                       CH.sub.2 Ph                                                                          0 4-phenylbenzyl                                                                             3,3-diphenylpropionyl                        19 butyl   CH.sub.2 Ph                                                                          1 4-phenylbenzyl                                                                             3,4-di-Cl-phenylacetyl                       20 butyl   CH.sub.2 Ph                                                                          0 (3,4,5-tri-OMe)benzyl                                                                      (3,4,5-tri-OMe-phenyl)propionyl              21 methyl  CH.sub.2 Ph                                                                          0 3,4-di-Cl-benzyl                                                                           EtOC(O)(CH.sub.2).sub.4 C(O)                 22 butyl   CH.sub.2 Ph                                                                          0 EtOC(O)(CH.sub.2).sub.4 C(O)                                                               3,4,5-tri-OMe)benzoyl                        __________________________________________________________________________     ##STR29##                                                                    Entry R.sup.1  R.sup.3 R.sup.6     R.sup.7                                    __________________________________________________________________________    23    butyl    CH.sub.2 Ph                                                                           4-phenylbenzyl                                                                            phenylacetyl                               24    2-pyridinylmethyl                                                                      CH.sub.2 Ph                                                                           Me.sub.2 CHCH.sub.2                                                                       3-phenoxybenzoyl                           25    3-pyridinylmethyl                                                                      CH.sub.2 CH(Me).sub.2                                                                 propionyl   3,3-diphenylpropionyl                      26    3-pyridinylmethyl                                                                      CH.sub.2 Ph                                                                           3,5-di-CF.sub.3 -phenylacetyl                                                             3,3-diphenylpropionyl                      __________________________________________________________________________     ##STR30##                                                                 

We claim:
 1. A compound of Formula Iwherein: R¹ and R³ are independentlychosen from the group consisting of alkyl, alkoxyalkyl2-pyridinylmethyl, 3-pyridinylmethyl and arylalkyl; R² is H orS--C(O)--L--;wherein: S is a solid support; and --L-- is a linker ofFormula (a) ##STR31## wherein the left-hand bond is the point ofattachment to --C(O)-- and the right-hand bond is the point ofattachment to the amide nitrogen of Formula I; and Y is --C(O)R⁵ whereinR⁵ is ##STR32## wherein x is 0 or 1; and R⁶ and R⁷ are independentlychosen from the group consisting of substituted alkyl, alkylcarbonyl andsubstituted alkylcarbonyl.
 2. A compound according to claim 1 wherein R²is hydrogen.
 3. A compound according to claim 2 whereinR¹ is chosen fromthe group consisting of methyl, benzyl, butyl, 3-phenylpropyl,3-methoxypropyl, 2-pyridinylmethyl and 3-pyridinylmethyl; R⁶ is chosenfrom the group consisting of 3-pyridinylmethyl, phenylethoxyethyl,3,4,5-trimethoxybenzyl, 4-acetamidobenzyl, 4-phenylbutyl,3,4-dichlorobenzyl, 4-phenylbenzyl, 3-phenylpropyl, ethyl adipoyl,3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl, isobutyl, propionyland 3,5-di(trifluoromethyl)phenylacetyl; and R⁷ is chosen from the groupconsisting of 4-isopropoxybenzoyl, nicotinoyl, 3,4,5-trimethoxybenzoyl,3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl,3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl, phenylacetyl,3,4-dichlorophenylacetyl and ethyl adipoyl.
 4. A compound according toclaim 3 whereinR¹ is chosen from the group consisting of methyl, benzyl,butyl, 3-phenylpropyl and 3-methoxypropyl; R⁶ is chosen from the groupconsisting of 3-pyridinylmethyl, phenylethoxyethyl,3,4,5-trimethoxybenzyl, 4-acetamidobenzyl, 4-phenylbutyl, ethyl adipoyl,3,4-dichlorobenzyl, 4-phenylbenzyl, 3,5-bis(trifluoromethyl)benzyl,3-phenylpropionyl and 3-phenylpropyl; and R⁷ is chosen from the groupconsisting of 4-isopropoxybenzoyl, nicotinoyl, 3,4,5-trimethoxybenzoyl,3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl,3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl,3,4-dichlorophenylacetyl, and ethyl adipoyl.
 5. A compound according toclaim 1 wherein R² is S--C(O)--L--.
 6. A compound according to claim 5wherein:R¹ is chosen from the group consisting of methyl, benzyl, butyl,3-phenylpropyl, 3-methoxypropyl, 2-pyridinylmethyl and3-pyridinylmethyl; R⁶ is chosen from the group consisting of3-pyridinylmethyl, phenylethoxyethyl, 3,4,5-trimethoxybenzyl,4-acetamidobenzyl, 4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl,3-phenylpropyl, ethyl adipoyl, 3,5-bis(trifluoromethyl)benzyl,3-phenylpropionyl, isobutyl, propionyl and3,5-di(trifluoromethyl)phenylacetyl; and R⁷ is chosen from the groupconsisting of 4-isopropoxybenzoyl, nicotinoyl, 3,4,5-trimethoxybenzoyl,3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl,3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl, phenylacetyl,3,4-dichlorophenylacetyl and ethyl adipoyl.
 7. A compound according toclaim 6 whereinR¹ is chosen from the group consisting of methyl, benzyl,butyl, 3-phenylpropyl and 3-methoxypropyl; R⁶ is chosen from the groupconsisting of 3-pyridinylmethyl, phenylethoxyethyl,3,4,5-trimethoxybenzyl, 4-acetamidobenzyl, 4-phenylbutyl, ethyl adipoyl,3,4-dichlorobenzyl, 4-phenylbenzyl, 3,5-bis(trifluoromethyl)benzyl,3-phenylpropionyl and 3-phenylpropyl; and R⁷ is chosen from the groupconsisting of 4-isopropoxybenzoyl, nicotinoyl, 3,4,5-trimethoxybenzoyl,3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl,3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl,3,4-dichlorophenylacetyl and ethyl adipoyl.